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Mar 2021 Nature Communications

Alternative lengthening of telomeres is notsynonymous with mutations in ATRX/DAXX.


de Nonneville A, Reddel RR


The PCAWG Consortium has recently released an integrativere-analysis of a large set of tumor whole genome sequence(WGS) data from 2658 cancer patients across 38 differentprimary tumor sites1. In a companion paper, Sieverling et al. builta random forest classifier for the telomere maintenance mechan-ism (TMM) by regarding truncating ATRX or DAXX alterations,referred to as ATRX/DAXXtrunc, vs. TERT modifications(TERTmod; i.e., promoter mutations ± amplifications ± structuralvariations), as indicators of alternative lengthening of telomeres(ALT) vs. telomerase2. We show here that equating ATRX/DAXXtruncand TERTmodwith ALT and telomerase, respectively,results in TMM predictions which do not correlate well with TMMassay data. Although ATRX/DAXXtruncmutations are associatedwith TMM, most tumors do not harbor them and they are het-erogeneously distributed in ALT-positive (ALT+)tumorsofdifferent types, as are TERTmodin telomerase-positive tumors3–6,making these mutations an insufficient basis for building a clas-sifier in a large-scale pan-cancer study.

Here, we provide a new analysis of the PCAWG data, based onC-circle assay (CCA)7data that are available for a subset of thesetumors3. We show that the Sieverling et al. score overestimatesthe proportion of ALT associated with ATRX/DAXXtruncandmisclassifies ALT tumors when these mutations are absent. Wealso show some telomere variant repeats (TVR) correlate withATRX/DAXXtruncmutations, regardless of TMM. Finally, wepropose a new classifier to identify ALT tumors in the PCAWGcohort.